Scientists Discover Potential Marker of Immunotherapy Success in Lung Cancer Patients

Lung cancer has the highest death rate of all cancers, and treatment options are extremely limited, especially for patients with oncogenic mutations in the KRAS gene. Much hope has been placed in the approval of immune checkpoint inhibitors, but the reality is that some patients respond very well to this treatment while it is totally ineffective in others. In an article that has just appeared in Science Translational Medicine, a MedUni Vienna research group led by Herwig Moll (Center for Physiology and Pharmacology) identified a potential marker for the success of immunotherapy in lung cancer patients and explained the underlying molecular processes.

K-Ras is a monomeric G protein that plays a key role in the growth of malignant tumors. Lung carcinomas with the KRAS mutation often occur in chronically inflamed lungs, especially in heavy smokers. Inflammatory processes promote the growth of cancer cells. The research group has now shown that the expression of the highly anti-inflammatory protein A20, formed in the organism itself, is often very low in these malignant cells and that there is a direct correlation between the expectation of life of a patient and the expression of this protein. .

Moll explains: “In both humans and animal models, the loss of A20 leads to degraded immune surveillance of cancer cells. Cancer cells with low levels of A20 are able to escape detection by the immune system. This results in significantly faster tumor growth.

During this study, co-funded by the MedUni Vienna Cancer Research Initiative and associated with the Comprehensive Cancer Center Vienna, the research team found that this is primarily an increased sensitivity of cancer cells to the immunomodulatory cytokine interferon gamma which is responsible for this. In addition, tumor cells with downregulated A20 responded particularly well to immune checkpoint inhibitors, as did patients with melanoma (skin cancer) with a similar gene expression structure.

In A20, we discovered a previously unknown tumor suppressor in lung cancer, the loss of which as an immune checkpoint contributes to the development of this malignant disease. ”

Emilio Casanova, co-author, Institute of Pharmacology

Since patients with low A20 expression have few anti-tumor immune cells and therefore, at an advanced stage, express little of the important PD-L1 immune checkpoint molecule, these patients may be excluded from directed immunotherapies. against PD-L1. Indeed, the strength of expression of this molecule is currently considered as an aid in deciding whether or not to treat them with immune checkpoint inhibitors. “Based on our results and the available data on melanoma patients, we are confident that we have identified a group of lung cancer patients who would actually benefit from this immunotherapy. Excluding such treatment would significantly reduce the survival rate of these patients.

In another study, researchers want to know if it is possible to manipulate the expression of A20 in cancer cells, in order to intensify the effect of immunotherapies. “However, smoking remains the most easily avoided risk factor for lung cancer. We therefore need to support laws aimed at protecting the general public from inhaling harmful smoke, while appealing to the personal responsibility of the people of abstain from smoking altogether, ”Moll said. . According to experts from MedUni Vienna, it is nevertheless important to continue to research new therapeutic approaches to improve the quality of life and the chances of survival of those affected.